Substituted mercaptoacetamidocephalosporins

ABSTRACT

7-Cyanomethylmercaptoacetamidocephalosporins, 7cyanomethylsulfinylacetamidocephalosporins, and 7cyanomethylsulfonylacetamidocephalosporins, which have antibacterial activity, are disclosed.

United States Patent 1191 DeMarinis May 13, 1975 SUBSTITUTED MERCAPTOACETAMIDOCEPHALOSPO- RINS [75} Inventor: Robert M. DeMarinis, King of Prussia, Pa.

[73] Assignee: SmithKline Corporation,

Philadelphia, Pa.

221 Filed: Aug. 17, 1973 21 Appl. No.: 389,407

[521' U.S. Cl. 260/243 C; 424/246 [51] Int. Cl C07d 99/24 [58] Field of Search 260/243 C [56] References Cited UNITED STATES PATENTS 3,641,021 2/1972 Ryan 260/243 C Primary E.\'aminer,Nicholas S. Rizzo Attorney, Agenl, 0r Firm-William H. Edgerton; Stuart R. Suter; Alan D. Lourie s7 ABSTRACT 12 Claims, No Drawings SUBSTITUTED MERCAPTOACETAMIDOCEPHALOSPORINS This invention relates to cephalosporin compounds with cyanomethylmercaptoacetamido or the mono or dioxidized derivative at position 7 of the cephem nucleus. These compoundshave antibacterial activity.

A wide variety of acyl groups have been used at position 7 of cephalosporin in the search for improved antibiotics. For example. 7-alkylmercaptoacetamidoceph Het includes the N-oxide derivatives of the heterocyclic systems named where such derivatives are possible, for example. pyi'idyl-Noxide.

A preferred group of compounds are those where X is SHet. Particularly preferred are compounds where Het is tctrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, or pyridyl, unsubstituted or substituted. Preferred substituents are alkyl of C -C hydroxy or mercapto.

Also within the scope of the invention are the nontoxic pharmaceutically acce table salts of the acids dealosporanic acids have been disclosed in US. Pat. No. fined by m6 formula given agove. Many salts and met and Othersl Also .7'pmpafgylmcrcap ods of preparation are known within the art. toacetamidocephalosporins are disclosed ll'lUS. Pat. The compounds of the invention are prepared by my 1728531 However. l l9 i ylation of a 7-aminocephalosporanic acid or a deriva- (iyamimethylmercaptqacetamdo or its oxldzed, derwa' tive thereof. The acylation agents are cyanomethylmer' ni; m the lacy] moleiy .have i been descnbed'. captoacetic acid, cyanomethylsulfinylacetic acid, and f iz $2233: of this mventlon have the followmg cyanomethylsulfonylacetic acid or their activated derivatives. Common methods known to one skilled in the art such as mixed anhydride, acid halide, or activated ester may be used to activate the carboxyl group. Also a coupling reagent such as dicyclohexylcarbodiimide or i N,N'-carbonyldiimidazole may be used to acylate es- NCCHZS l/ ters of the cephalosporin nucleus.

The laminocephalosporanic acids and derivatives H x are known in the art. Cyanometihylmercaptoacetic acid 6 2 is prepared by reaction of chloroacetonitrile and mer- COOH captoacetic acid in the presence of a base. Preparation of the other acylation agents or activated derivatives are done by standard methods or described herein. The compounds of this invention have broadspectrum antibacterial activity with minimum inhibitory where concentrations (MIC) ranging from .0.2 to 200 u/ml n is 0, l, or 2; when determined by standard agar inclusion methods. X is hydrogen, a'cetoxy, OCH, SCH or SHet; and Table 1 shows MlCs for a variety of compounds within Het is a 5 or 6 membered heterocyclic ring contain the scope of this invention against representative ing carbon and l-4 atoms selected from the group Gram-positive and Gram-negative bacteria. consisting of N, O, and S, unsubstituted or substi- The compounds of this invention are formulated and tutcd with one or two substituents selected from administered by injection in the same manner as other the group consisting of alkyl of C -C alkoxy of 40 cephalosporins in dosages of from 250 to 1,000 mg. C -C allyloxy, oxide, halogen, carboxamido, car- The dosage is dependent on the age and weight of the boxyl, carbalkoxy of C -C mercapto, methylthio, subject and on the infection being treated and can be trifluoromethyl, hydroxy, amino, alkylamino and determined by those skilled in the art based on the data dialkylamino, each undefined alkyl having l-6 cardisclosed herein and experience with known caphalosbon atoms. P

TABLE 1 MIC m1 5 s E 5 a 5 q I n q m u w 8 g g mo 3 a go 3 co 3o s .3... o o 35 a5 3; a3 38 3 33; 3.4 .2 .113 32 E8 E8 32 7-15. 6 I13 553 33 52 3 8% 82 82 A54 .62 8o 303 3" Eu iiu Compound Q E .32 3:4 :8 h s Number mm: mm m m z=z mi saw mm n ma. mg rm: an:

* See Table 2 or structures TA 8 L E 2 Compound No. n X

79336 acctoxy 21436 0 S-mcthyll.3,4-

thiadiazol-Z-ylthio 94436 0 l-mcthyltctrazol-S- yllhio 90246 2 acetoxy 09346 2 S-mcthyll ,3,4- thiadiazol-Z-ylthio 72346 2 l-methyltetrazol-- ylthio The compounds are formulated in the same manner as other cephalosporins which are administered parenterally. The daily dose, which may be divided, may range from l-5 g depending on the subect and the infection being treated.

The following examples illustrate the invention but are not to be construed as limiting the scope thereof.

PREPARATION l N-Hydroxysuccinimidyl cyanomethylmercaptoacetate To a solution of cyanomethylmercaptoacetic acid (7.9 g, 60 mmol) and N-hydroxysuccinimide (6.9 g, 60 mmol) in tetrahydrofuran (150 ml) was added in portions 21 solution of dicyclohexylcarbodiimide (12.4 g, 60 mmol) in tetrahydrofuran (35 ml). The reaction was stirred overnight at room temperature. The solid urea was filtered and washed with THF, the filtrate was concentrated to 25 ml, and additional urea was removed. The solutionwas evaporated and the product was recrystallized from chloroform; mp 909l.

PREPARATION 2 N-Hydroxysuccinimidyl cyanomethylsulfinylacetate PREPARATION 3 Cyanomethylsulfonylacetic acid To acooled, stirred solution of cyanomethylmercaptoacetic acid (26.2 g, 0.2 mol) in tetrahydrofuran (300 ml) was added dropwise a solution m-chloroperbenzoic acid (85%, 99 g, 0.5 mol) in tetrahydrofuran (400 ml). The reaction was stirred at 0 for minutes and then overnight at room temperature. The solvent was removed and the residue was washed with water (3 X 200 ml). The aqueous solution was allowed to stand 2 days, the precipitated solid wasfiltered, and the filtrate was lyophilized to give the product; mp l04l05.

EXAMPLE 1 7-Cyanomethylmercaptoacetamidocephalosporanic acid Triethylamine was added to a suspension of 7-ACA (2.72 g, 10 mmol) in dimethylformamide ml) until solution was effected. To this solution was added N- hydroxysuccinimidyl cyanomethylmercaptoacetate (2.28 g, 10 mmol) and the reaction was stirred at room temperature until tlc analysis indicated the reaction was completed (ca. 3 hours). The reaction was poured slowly with vigorous stirring into ether (1,000 ml) and the precipitated solid was removed by filtration through filter aid. The filter cake was stirred with water (400 ml) containing triethylamine (4 ml) and then was filtered. The filtrate was acidified to pH 2.5 and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated to a small volume (ca. 20 ml) which contained the title product. A solution of sodium 2-ethylhexanoate was added followed by ether. The precipitated sodium salt of the product was collected, mp 178-9(dec).

EXAMPLE 2 7-Cyanomethylmercaptoacetamido-3-( S-methyl-l ,3 ,4- thiadiozol-Z-ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(5-methyll ,3,4-thiadiazol-2- ylthiomethyl)-3-cephem-4-carboxylic acid (3.44 g, 10 mmol) was acylated with N-hydroxysuccinimidyl cyanomethylmercaptoacetate (2.28 g, 10 mmol) according to the procedure of Example 1 to give the title compound. I

EXAMPLE 3 7-C yanomethylmercaptoacetamido-3-(1-methyltetrazol-Sylthiomethyl)-3-cephem-4-carboxylic acid The title compound was prepared by the reaction of 7-amino-3-( l-methyltetrazol-S-ylthiomethyl )-3- cephem-4-carboxylic acid (3.28 g, 10 mmol) and N- hydroxysuccinimidyl cyanomethylmercaptoacetate (3.4 g, 15 mmol) by the procedure of Example 1.

EXAMPLE 4 When an equimolar amount of the following 7- amino-3-heterocyclicthiomethyl 3-cephem-4- carboxylic acids are substituted for 7-aminocephalosporanic acid in the procedure of Example 1, the corresponding 7-cyanomethylmercaptoacetamido-3- heterocyclicthiomethyl-3-cephem-4-carboxylic acid is 7-Amino-3-(4-methyl-l ,2,4-triazol-3-ylthiomethyl 3-cephem-4-carboxylic acid 7-Amino-3-(4,5-dimethyl l,2,4triazol-3 ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(2,5-dimethyl-l,2,4-triazol-3- ylthiomethyl)-3-cephem4-carboxylic acid 7-Amino-3-(4-methyl-5-trifluoromethyl-l ,2,4-

triazl-3-ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(5-ethyl-1,2,4-triazol-3-ylthiomethyl)-3- cephem-4-carboxylic acid 7-Amino-3-(4-ethyll ,2,4-triazol-3-ylthiomethyl)-3- cephem-4-carboxylic acid 7-Amino-3-( l-methyl-l ,2,4-triazol-5-ylthiomethyl)- 3-cephem-4-carboxylic acid 7-Amino-3-( l-methyl-l ,2,4-triazol-3-ylthiornethyl)- 3-cephem-4-carboxylic acid 7-Amino-3-( l-ethyl'l ,2,4-triazol-5-ylthiomethyl)-3- cephem-4-carboxylic acid 7-Amino-3-( l-ethyl-l ,2,4-triazol-3-ylthiomethyl)-3- cephem-4-carboxylic acid 7-Amino-3-(4-allyl-l ,2,4-triazol-3-ylthiomethyl)-3- cephem-4-carboxylic acid 7-Amino-3-(5-methoxymethyl-l,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(5-cyclopropyll ,2,4-triazol3- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-( 5-bromo-l ;2,4-triazol-3-ylthiomethyl)- 3-cephem-4-carboxylic acid 7-Amino-3-( 5-hydroxy-4-rnethyl-l ,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino3-(5-hydroxy-4-ethyl-l,2,4-triazo l-3- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(5-hydroxy-1,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid 7 7-Amino3-( l,2,3-triazol-4-ylthiomethyl)-3-cephem- 4-carboxylic acid I 7-Amino-3-( l-methyl-l ,2,3-triazol-S-ylthiomethyl) 3-cephem-4-carboxylic acid 7-Amino-3-( 4-methyl-l ,2,3-triazol-5-ylthiomethyl)- 3-cephem-4-carboxylic acid 7-Amin0-3-( l,3,4-oxadiazol-2-ylthiomethyl)-3- cephem-4-carboxylic acid 7 7-Amino-3-( S-methyl-l ,3,4-oxadiazol-2- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(4-pyrimidylthiomethyl)-3-cephem-4- carboxylic acid 7-Amino-3-( 2-pyrazinylthiomethyl )-3-cephem-4- carboxylic acid 7-Amino-3-(3-pyridylthiomethyl)-3-cephem-4- carboxylic acid 7-Amino-3-(4-pyridylthiomethyl)-3-cephem-4- carboxylic acid 7-Amin0-3-( l-oxide-2-pyridylthiomethyl)-3- cephem-4-carboxylic acid.

EXAMPLES 7-Cyanomethylsulfonylacetamidocephalosporanic acid To a stirred solution of t-butyl 7- aminocephalosporanate (3.3 g, 10 mmol) and cyanomethylsulfonylacetic acid (1.6 g, 10 mmol) in tetrahydrofuran (30 ml) was added dropwise a solution of dicyclohexylcarbodiimide (2.1 g, 10 mmol) in tetrahydrofuran ml). The reaction was stirred at room temperature for 4 hours and filtered. The filtrate was evaporated and the residue was chromatographed on silica gel g) with 1:1 ethyl acetate: benzene as eluent. The purified ester (1.57 g, 3.3 mmol) in acetonitrile (15 ml) was warmed to effect complete solution and then trifluoroacetic acid (15 ml) was added. The reaction was allowed to stand for 4 hours and the precipitated title product was collected, triturated with acetonitrile and ether and dried.

EXAMPLE 6 7-Cyanomethylsulfonylacetamido-3-(S-methyl-1,3,4- thiadiazol-Z-ylthiornethyl)3-cephem-4-carboxylic acid -t-Butyl 7-amino-3-(5-methyl-l ,3,4-thiadiazol-2- ylthiomethyl)-3-cephem-4carboxylate (8.0 g, 20 mmol), cyanomethylsulfonylacetic acid (3.3 g, 20 mmol) and dicyclohexylcarbodiimide (4.1 g, 20 mmol) were reacted by the procedure of Example 5. The crude ester was chromatographed on silica gel using ethyl acetate as eluent. The purified t-butyl ester (6.2 g) was dissolved in hot acetonitrile (40 ml) and trifluoroacetic acid (40 ml) was added. The solution was allowed to stand 2.5 hours and then was added slowly to ether ml) with stirring. The precipitated title compound was collected, triturated with ether and dried.

EXAMPLE 7 7-Cyanomethylsulfonylacetamido-3-( l -methyltetrazol- S-ylthiomethyl)-3-cephem-4-carboxylic acid t-Butyl 7-amino-3-( l-methyltetrazol-S- ylthiomethyl)-3-cephem-4-carboxylate (5.75 g, l5 mmol), cyanomethylsulfonylacetic acid (2.45 g, 15 mmol), and dicyclohexylcarbodiimide (3.1 g, 15 mmol) were reacted as in Example 6. The t-butyl ester was treated with trifluoroacetic acid for 20 minutes as in Example 6, to give the title compound.

EXAMPLE 8 When an equimolar amount of the t-butyl esters of the following 7-amino-3-heterocyclicthiomethyl-3- cephem-4-carboxylic acids are substituted for t-butyl 7-amino-3-( S-methyl-l ,3 ,4-thiadiazol-2-ylthiomethyl)- 3-cephem-4-carboxylate in the procedure of Example 6, the corresponding 7-cyanomethylsulfonylacetamido- 3-heterocyclicthiomethyl-3-cephem-4-carboxylic acid is formed.

7-Amino-3-(tetrazol-S-ylthiomethyl)-3-cephem-4- carboxylic acid 7-Amin0-3-( l ,3,4-thiadiazol-2-ylthiomethyl)-3- cephem-4-carboxylic acid 7-Amino-3-( S-trifluoromethyl-l ,3,4-thiadiazol-2- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amin0-3(5-ethyl-l ,3 ,4-thiadiaz0l-2- ylthiomethyl)-3-cephem-4carboxylic acid 7-Arnino-3-(5-n-butyl-l ,3.4-thiadiazol-2- .ylthiolmethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(S-dimethylaminol ,3,4-thiadiazol-2 ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(5-mercapto-l ,3 ,4-thiadiazol-2- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-( 3-methylthio-1,2,4-thiadiazol-5- ylthiomethyl)-3-cephem-4 carboxylic acid 7-Amin0 -3-(3-methyl-l ,2,4-thiadiazol-5- ylthiomethyl)3-cephem-4-carboxylic acid 7-Amino-3-( 1 ,2,4-triazol-3-ylthiomethyl)-3-cephem- 4-carboxylic acid 'F-Amirm-B-(S-methyll ,ZA-triazol-3'ylthiomethyl 3-cephem-4-carboxylic acid 7-Amino-3-(4methyll ,2,4-triazol-3-ylthiomethyl)- 3-cephem-4-carboxylic acid 7-Amino-3-(4,5-dimethyl-I,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(2,5-dimethyl-1,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(4-methyl-5-trifluoromethyl-1,2,4-

triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-( 5-ethyl-l ,2,4-triazol-3-ylthiomethyl)-3- cephem-4-carboxylic acid 7-Amino-3-(4-ethyll ,2,4-triazol-3-ylthiomethyl)-3- cephem-4-carboxylic acid 7-Amino-3-( l-methyl-l ,2,4-triazl-5-ylthiomethyl)- 3-cephem-4-carboxylic acid 7-Amino-3-( l-methyl-l ,2,4-triazol-3-ylthiomethyl)- 3-cephem-4-carboxylic acid 7-Amino-3-( l-ethyll ,2,4-triazol-S-ylthiomethyl)-3- cephem-4-carboxylic acid 7-Amino-3-( l-ethyl-l ,2,4-triaz0l-3-ylthiomethyl)-3- cephem-4-carboxylic acid 7-Amino-3-(4-allyl-l ,2,4-triazol-3-ylthiomethyl)-3- cephem-4-carboxylic acid 7-Amino-3-(S-methoxymethyl-l ,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(S-cyclopropyl-l ,2,4-triazol-3- ylthiomethyl)-3-eephem-4-carboxylic acid 7-Amino-3-( 5-bromo-l ,2,4-triazol-3-ylthiomethyl)- 3-cephem-4-carboxylic acid 7-Amino-3-( 5-hydroxy-4-methyll ,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(5-hydroxy-4-ethyll ,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-( 5-hydroxy-l ,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-( l-methyl-l ,2,3-triazol-5-ylthiomethyl)- 3-cephem-4-carboxylic acid 7-Amino-3-( l,3,4-0xadiazol-2-ylthiomethyl)-3- cephem-4-carboxylic acid 7-Amino-3-(5-methyl-l ,3,4-oxadiazol-2- ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(4-pyrimidylthiomethyl)-3-cephem-4 carboxylic acid 7-Amino-3-( 2-pyrazinylthiomethyl)-3-cephem-4- carboxylic acid 7-Amino-3-(3-pyridylthiomethyl)-3-cephem-4- carboxylic acid 7-Amino-3-(4-pyridylthiomethyl)-3-cephem-4- carboxylic acid 7-Amino-3-( l-oxide cephem-4-carboxylic acid -2-pyridylthiomethyl)-3- EXAMPLE 9 When 7-aminocephalosporanic acid, 7-amino-3-(5- methyl-l ,3,4-thiadiazol-5-ylthiomethyl)-3-cephein-4- carboxylic acid, and 7-amino-3-( l-methyltetrazol-S- ylthiomethyl)-3-cephem-4-carboxylic acid are acylated with- N-hydroxysuccinimidyl cyanomethylsulfinylaeetate according to the procedure used in Example 1 the following compounds are obtained:

7-cyanomethylsulfinylacetamidocephalosporanic acid 7-cyanomethylsulfinylacetamido-3-(S-methyll ,3 ,4-

thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid '1' cyanomethylsulfinylacetamido-3-( lmethyltetrazol-5-ylthiomethyl)-3-cephem-4- carboxylic acid.

EXAMPLE l0 When an equimolar amount of the 7-amin0-3- heterocyclicthiomethyl-3-cephem-4-carb.oxylic acids enumerated in Example 4 are substituted for 7-amino- 3-( S-methyll ,3 ,4-thiadiazol-2-ylthiomethyl )-3- cephem-4-carboxylic acid in the procedure of Example 9, the corresponding 7-cyanomethylsulfinylacetamido- 3-heterocyclicthiomethyl-3-cephem-4-carboxylic acid is formed.

EXAMPLE ll Cyanomethylsulfonylacetic acid is reacted with N- hydroxysuccinimide according to the procedure of Preparation 1 to give the activated ester which is reacted at once with 7-amino-3-(l,2,3-triazol-4- ylthiomethyl)-3-cephem-4-carboxylic acid to give 7- cyanomethylsulfonylacetamido-3-( l .2,3-triazol-4- ylthiomethyl)-3-cephem-4-carboxylic acid. Cyanomethylsulfonylacetamido-3-(4-methyl-l ,2,3- triazol-5-ylthiomethyl-3-cephem-4-carboxylic acid is prepared in a similar manner.

EXAMPLE 12 When 7-aminodesacetoxycephalosporanic acid (7- ADCA) is acylated according to the procedure of Example l with N-hydroxysuccinimidyl cyanomethylmercaptoacetate and N-hydroxysuccinimidyl cyanomethylsulfinylacetate, 7- cyanomethylmercap'toacetamido-3-methyl-3-cephem- 4-carboxylic acid and 7- cyanomethylsulfinylacetamido-3-methyl-3-cephem-4- carboxylic acid are obtained.

When the t-butyl ester of 7-ADCA is acylated with cyanomethylsulfonylacetic acid by the procedure of Example 5, 7-cyanomethylsulfonylaeetamido-3- methyl-3-cephem-4-carboxylic acid is obtained.

EXAMPLE 13 EXAMPLE l4 Substitution of 7-amino-3-methylmercaptomethyl3- cephem-4-carboxylic acid or its t-butyl ester for 7- amino-3-methoxymethyl 3-cephem-4-carboxylic acid or its t-butyl ester in Example 12 gives the following products:

7-cyanomethylmercaptoacetamido-3- methylmercaptomethyl-3-cephem4-carboxylic acid 7-cyanomethylsulfinylacetamido-3- methylmercaptomethyl-3-cephem-4-carboxylic acid 7-cyanomethylsulfonylacetamido-IS- methylmercaptomethyl-3-cephem-4-carboxylic 5 acid EXAMPLE An injectable pharmaceutical composition is prepared by dissolving cyanomethylsulfonylacetamido-3-( l-methyltetrazol-5- ylthiomethyl)-3-cephem-4-carboxylate in sterile water or sterile normal saline solution (l2 ml). All other cephalosporins within the formula 1 including each compound enumerated in the above examples are formulated in a similar manner.

100-500 mg of sodium 7- I claim: 1. A compound of the formula NCCH S (O) CH C0 OOH where or a non-toxic pharmaceutically acceptable thereof.

2. A compound as claimed in claim 1 where n is 0.

3. A compound as claimed in claim 1 where n is l.

4. A compound as claimed in claim 1 where n is 2.

5. A compound as claimed in claim 2 where X is SHet and Het is tetrazolyl, thiadiazolyl, triazolyl, oxadiazolyl, or pyridyl, unsubstituted or substituted with one or two substituents selected from the group consisting of alkyl of C -C hydroxy, and mercapto.

6. A compound as claimed in claim 3 where X is SHet and Het is tetrazolyl, thiadiazolyl, triazolyl, oxadiazolyl, or pyridyl, unsubstituted or substituted with one or two substituents selected from the group consisting of alkyl of C -C hydroxy, and mercapto.

7. A compound as claimed in claim 4 where X is SHet and Het is tetrazolyl, thiadi'a'z'olyl, triazolyl, oxadiazolyl, or pyridyl, unsubstituted or substituted with one or two substituents selected from the group consisting of alkyl of C -C hydroxy, and mercapto.

8. A compound as claimed in claim 5 being the compound 7-cyanomethylmercaptoacetamido-3-(5- methyl-l ,3,4-thiadiazol-Z-ylthiomethyl)-3-cephem-4- carboxylic acid.

9. A compound as claimed in claim 5 being the compound 7-cyanomethylmercaptoacetamido-3-( lmethyltetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid.

10. A compound as claimed in claim 6 being the compound 7-cyanomethylsulfinylacetamido-3-( lmethyltetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid.

11. A compound as claimed in' claim 7 being the compound 7-cyanomethy'lsulfonylacetamido-3-(5- methyl-1,3 ,4-thiadiazol-2-ylthiomethyl)-3-cephem-4- carboxylic acid.

12. A compound as claimed in claim 7 being the compound 7-cyanomethylsulfonylacetamido-3-( lmethyltetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid.

salt 

1. A COMPOUND OF THE FORMULA
 2. A compound as claimed in claim 1 where n is
 0. 3. A compound as claimed in claim 1 where n is
 1. 4. A compound as claimed in claim 1 where n is
 2. 5. A compound as claimed in claim 2 where X is SHet and Het is tetrazolyl, thiadiazolyl, triazolyl, oxadiazolyl, or pyridyl, unsubstituted or substituted with one or two substituents selected from the group consisting of alkyl of C1-C6, hydroxy, and mercapto.
 6. A compound as claimed in claim 3 where X is SHet and Het is tetrazolyl, thiadiazolyl, triazolyl, oxadiazolyl, or pyridyl, unsubstituted or substituted with one or two substituents selected from the group consisting of alkyl of C1-C6, hydroxy, and mercapto.
 7. A compound as claimed in claim 4 where X is SHet and Het is tetrazolyl, thiadiazolyl, triazolyl, oxadiazolyl, or pyridyl, unsubstituted or substituted with one or two substituents selected from the group consisting of alkyl of C1-C6 , hydroxy, and mercapto.
 8. A compound as claimed in claim 5 being the compound 7-cyanomethylmercaptoacetamido-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid.
 9. A compound as claimed in claim 5 being the compound 7-cyanomethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem -4-carboxylic acid.
 10. A compound as claimed in claim 6 being the compound 7-cyanomethylsulfinylacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem -4-carboxylic acid.
 11. A compound as claimed in claim 7 being the compound 7-cyanomethylsulfonylacetamido-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid.
 12. A compound as claimed in claim 7 being the compound 7-cyanomethylsulfonylacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem -4-carboxylic acid. 